Biologically Active Cannabidiol Analogs

ABSTRACT

Biologically active cannabidiol analogs comprising a compound of the formula 
     
       
         
         
             
             
         
       
     
     wherein one of R 1  or R 2  or both is/are the residue of a moiety formed by the reaction of an amino group of the amino acid ester of R 1  or R 2  or both with a dicarboxylic acid or a dicarboxylic acid derivative and the other R 1  or R 2  (in the case of the mono) is the residue of a dicarboxylic acid or dicarboxylic acid derivative or Hydrogen (H), (i.e. underivatized), and salts thereof. These CBD analogs are be useful in pain management in oncology and other clinical settings in which neuropathy is presented. Furthermore, these CBD-analogs are useful in blocking the addictive properties of opiates.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No. 16/073,766filed on Jul. 27, 2018, which is a National Stage Entry of InternationalApplication No. PCT/US17/15366, filed on Jan. 27, 2017, which claimspriority to U.S. Provisional Application No. 62/289,184, filed on Jan.29, 2016, the disclosures of which are hereby incorporated by specificreference thereto.

FIELD OF THE INVENTION

The present invention is directed to the development of biologicallyactive cannabidiol analogs capable of being formulated intopharmaceutical compositions, and methods of using such compositions fora pharmacological benefit. In a further embodiment of the presentinvention biologically active CBD analogs possessed analgesic propertiesalone and in combination of a sub-analgesic dose of morphine incisplatin induced neuropathy. Furthermore, these analogs exhibitedblocking properties to opiate addiction.

BACKGROUND OF THE INVENTION

Cannabidiol (CBD) has a variety of pharmacological benefits, including,but not limited to anti-inflammatory, analgesic, anti-convulsant,anti-psychotic, anti-fibrosis, anti-scarring, anti-oxidant,neuroprotective, anti-infective, anti-cancer and immunomodulatoryeffects.

Cisplatin is a common chemotherapy used to treat a variety of cancers.Unfortunately, cisplatin has a dose limiting effect wherein 50-85% ofpatients develop peripheral neuropathy 3-6 months into treatment.Cisplatin-induced neuropathy (CIN) presents in a “stocking and glove”distribution causing tingling paresthesia, numbness, and allodynia(Paice, 2010; Amptoulach et al., 2011). Pain management for CIN includesanticonvulsant, antidepressant, and non-steroidal anti-inflammatorydrugs. These drugs prove to be well tolerated in patients but showlittle efficacy in treating CIN (Wolf et al., 2008; Amptoulach et al.,2011; Miltenburg et al., 2014).

While opioids can provide effective CIN pain relief, 76-96% of patientsreport aversive side effects that include sedation, nausea, and fatiguewhich limit usefulness and diminish patient quality of life (Guindon etal., 2008; Toth & Au, 2008). Added concerns of opioid therapy includetolerance, dose escalation, and dependence that can lead to withdrawalsymptoms upon CIN resolution (Kim et al., 2015). Collectively, theseobservations suggest a need to develop novel pharmacotherapies for CIN.

Cannabinoids (CB) are used in oncology settings to control nausea,weight loss, lack of appetite, and chemotherapy related pain (Alexanderet al., 2009). CB analgesia in both chronic and acute pain models ismediated through CB1 and CB2 receptors that are differentially expressedin the central and peripheral nervous systems (Chiou et al., 2013;Pisanti et al., 2013). An emerging body of literature supports thenotion that CB systems may also modulate CIN. For example, CB1 and CB2direct and indirect agonists attenuate tactile allodynia in rodentmodels of CIN (Vera et al., 2013; Guindon et al., 2012, Khasabova etal., 2012). However, like non-opioid therapies, CB compounds have modestefficacy and are of limited usefulness.

CB1 and opioid receptors are co-localized in pain pathways. Evidencesuggest a dual pharmacotherapy at these targets may increase CB-mediatedanalgesic effects (Wilson-Poe et al., 2008; Hall et al., 2005; Mansouret al., 1988; Basbaum et al., 1984). For example, the CB1 agonist THCshows synergistic effects with sub-analgesic doses of the mu opioidagonist morphine in a rat arthritic pain model (Cox et al., 2007).However, use of any CB1 agonist in oncology settings is unlikely due tothese compounds increasing the proliferation and growth of some tumorcells (Hall et al., 2005). Interestingly, other CB constituents thatshow low affinity to CB receptors also show synergistic effects with lowdose opioids. For example, cannabidiol (CBD) shows synergistic effectswith sub-analgesic doses of morphine in an acute pain model (i.e.,acetic acid writhing) but not against thermal pain (Walker et al.,2015). Whether a combined CBD-opioid pharmacotherapy could providehighly efficacious pain relief against cisplatin neuropathy is unknown.

Challenges in pain management in oncology settings lead to unnecessarysuffering, diminished quality of life, and in some instances, decreasedlife expectancy due to patients forgoing continued chemotherapytreatment. Current therapies against CIN are either only modestlyeffective or are fully effective but poorly tolerated.

SUMMARY OF THE INVENTION

Described herein are biologically active analogs of CBD that can beadministered by a wide variety of routes of administration including butnot limited to orally, transdermally or transmucosally (e.g. buccal,rectal, ocular, nasal) to a mammal, such as a human, for the treatmentof a medical condition such as pain, inflammation, epilepsy and oculardiseases, including but not limited to treatment of diseases of theretina (e.g. diabetic retinopathy and macular degeneration).

It has been discovered that biologically active CBD analogs containing anatural amino acid and a dicarboxylic acid moiety attached to one of thehydroxyl groups (with the amino acid linked to CBD through an esterlinkage and the dicarboxylic acid attached to the amino group of theamino acid in an amide linkage) with the other hydroxyl group free,result in higher than expected concentrations in vivo. Furthermore, theamino acid esters of CBD (di esters) must be reacted with a dicarboxylicacid, forming amide linkages with the free amine group of thecannabidiol-amino acid ester, to affect bioavailability in vivo.Exemplary CBD analogs can be represented by the following formulae:

The structures of CBD-divalinate-dihemisuccinate (1)CBD-mono-valinate-di-hemisuccinate (2) andCBD-monovalinate-hemisuccinate (3) are shown above.

In general, the analogs of the present invention can be represented bythe following generic formula I:

This formula I shows the structure for amino acid ester and/ordicarboxylic acid ester analogs wherein R₁ or R₂ or both is/are theresidue of a moiety formed by the reaction of the amino group of theamino acid ester with a dicarboxylic acid or a dicarboxylic acidderivative and R₁ or R₂ (in case of the mono amino acid ester) is theresidue of a dicarboxylic acid or dicarboxylic acid derivative or aHydrogen (H). Both R₁ and R₂ could be residues of moieties formed byreaction of the amine group of the amino acid ester at both sites with adicarboxylic acid.

The biologically active analogs of the invention can be formed fromamino acids including, for example, alanine, arginine, asparagine,aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine,isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine,threonine, tryptophan, tyrosine, valine, homoserine lactone, andnorleucine. By a “dicarboxylic acid” herein is meant an organic acidthat has two carboxyl groups (—COOH). The general molecular formula fordicarboxylic acids can be written as HO₂C—R—CO₂H, where R can bestraight chain or branched aliphatic or aromatic. Examples of suitabledicarboxylic acids in this invention include, but are not limited to,malonic acid, malic acid, glutaric acid, succinic acid, and phthalicacid. Dicarboxylic acids are reacted as their anhydrides and reactivederivatives of dicarboxylic acids such as, for example, dicarboxylicacid halides.

In a further embodiment of this invention, it has been found thatbiologically active CBD analogs such as described above including, forexample CBD-val-HS, possess several attributes that suggest thatbiologically active CBD analogs may be useful in pain management. First,CBD-val-HS has much better absorption and a longer biological half-lifethan CBD. More importantly, CBD-val-HS is biologically active and fullyefficacious as certain opioids in this CIN murine model. Collectively,these findings strongly argue that biologically active CBD analogs beconsidered in pain management in oncology and, perhaps, other clinicalsettings in which neuropathy is presented. Furthermore, thesebiologically active analogs of CBD were found to possess strongeractivity than CBD itself in blocking the morphine additive properties.

This suggests that a combination of these CBD derivatives with morphineand/or other opiates would have better analgesic activity than morphineand/or other opiates used alone while also preventing addiction tomorphine and/or other opiates cause by their extended use.

DETAILED DESCRIPTION OF THE INVENTION

The present invention comprises compounds of the formula I

wherein one of R₁ or R₂ or both is/are the residue of a moiety formed bythe reaction of an amino group of the amino acid ester of R₁ or R₂ orboth with a dicarboxylic acid or a dicarboxylic acid derivative and theother R₁ or R₂ (in the case of the mono) is the residue of adicarboxylic acid or dicarboxylic acid derivative or Hydrogen (H), (i.e.underivatized), and salts thereof.

The amino acid is can be, but not limited to the listed, alanine,arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid,glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, tryptophan, tyrosine andvaline.

The present invention still further comprises biologically activecompounds of the formula II:

wherein R′₁ and R′₂ or both are ester residue(s) of natural amino acidsand derivatives thereof and salts thereof.

The amino acid ester(s) is (are) selected from but not limited to one ofalanine, arginine, asparagine, aspartic acid, cysteine, glutamine,glutamic acid, glycine, histidine, isoleucine, leucine, lysine,methionine, phenylalanine, proline, serine, threonine, tryptophan,tyrosine and valine and derivatives thereof and salts thereof.

The compounds of the present invention can be described as compounds ofthe formula III:

wherein one of R₁ or R₂ or both is/are an amino acid ester residue of amoiety formed by the reaction of a carboxyl group of an amino acid withone or both phenolic groups of cannabidiol; or one of R₁ or R₂ or bothis/are an ester residue of a moiety formed by the reaction of a carboxylgroup of a dicarboxylic acid or dicarboxylic acid derivative with one orboth phenolic groups of cannabidiol; or one of R₁ or R₂ is the aminoacid ester residue of the reaction of the phenolic group of cannabidiolwith the carboxyl group of an amino acid and the other R₁ or R₂ is theester residue of the reaction of the phenolic group of cannabidiol withthe carboxyl of a dicarboxylic acid or dicarboxylic acid derivative; orone of R₁ or R₂ (in the case of the mono) is hydrogen (H), (i.e.underivatized) and the other R₁ or R₂ is an amino acid ester residue oran ester residue, and salts thereof.

One or both R₁ and R₂ is/are an amino acid ester moiety which is furtherreacted with a dicarboxylic acid or dicarboxylic acid derivative to forman amide moiety by the reaction of the amino group of the amino acidester with a carboxyl moiety of the dicarboxylic acid or dicarboxylicacid derivative.

The amino acid is any but not limited to one of alanine, arginine,asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine,histidine, isoleucine, leucine, lysine, methionine, phenylalanine,proline, serine, threonine, tryptophan, tyrosine and valine.

In one embodiment of the present invention R₁ or R₂ or both are esterresidue(s) of natural amino acids and derivatives thereof and saltsthereof.

Exemplary but not exclusive examples of the present invention include:the compound is CBD-Di-Glutaminate, CBD-Di-Hemisuccinate,CBD-Di-Alaninate Ester, CBD-Di-Alaninate-Di-Hemisuccinate,CBD-Di-Valinate, CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate,CBD-Mono-Valinate, CBD-Mono-Valinate-Mono-Hemisuccinate, orCBD-monovalinate-dihemisuccinate.

The present invention further encompasses a formulation foradministration of a biologically active CBD analog for the treatment ofa disease condition comprising a therapeutically effective amount of atleast one compound of formula I, II or III in an acceptable base orcarrier.

Exemplary but not exclusive formulations according to the presentinvention are formulations such as: 1) a formulation which is asuppository formulation in an acceptable suppository base; 2) aformulation which is an oral formulation (e.g. tablet, capsule orliquid); 2) a formulation which is a transmucosal delivery formulation;3) a formulation which is a topical ophthalmic formulation (e.g. aliquid, semi-solid or implant) for reducing the intraocular pressureand/or inflammation in the treatment of glaucoma and/or eye inflammationuveitis in an acceptable ophthalmic carrier; 4) an external or internaldepot delivery system for the eye (e.g. a pump, bio-erodible device, orsubcutaneous placed depot); 5) a topical formulation for application tothe skin (e.g. a lotion, gel, or ointment). The topical ophthalmicformulations can be for example a formulation which is a polymericocular film using lipid Nano particles.

A further embodiment of the present invention is a formulation foradministration of a biologically active CBD analog to a subject in needof treatment of a disease condition comprising a therapeuticallyeffective amount of at least one compound of per formula I in anacceptable base or carrier.

The formulation for administration of a biologically active CBD analogto a subject in need of treatment of a disease condition comprising atherapeutically effective amount of at least one compound wherein thecompound is CBD-Di-Glutaminate, CBD-Di-Hemisuccinate, CBD-Di-AlaninateEster, CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate,CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD-Mono-Valinate,CBD-Mono-Valinate-Mono-Hemisuccinate, orCBD-monovalinate-dihemisuccinate in an acceptable base or carrier.

The formulation can comprise a suppository formulation in an acceptablesuppository base; an oral formulation; a transmucosal deliveryformulation; a topical ophthalmic formulation; or an external orinternal depot delivery system.

A still further embodiment of the present invention is a method oftreating pain management comprising administering to a subject in needof such treatment an effective amount of at least one compound accordingformula I. The compound used in the present method is at least onecompound wherein the compound is CBD-Di-Glutaminate,CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester,CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate,CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD-Mono-Valinate,CBD-Mono-Valinate-Mono-Hemisuccinate, orCBD-monovalinate-dihemisuccinate in an acceptable base or carrier.

The pain management can be, for example, pain management in oncology orneuropathic pain management.

Additionally, the present invention relates to a method of blockingopiate additive properties and comprises administering to a subject inneed of such treatment an effective amount of at least one compound performula I. Preferably the compound used in this method is at least onecompound wherein the compound is CBD-Di-Glutaminate,CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester,CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate,CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD-Mono-Valinate,CBD-Mono-Valinate-Mono-Hemisuccinate, orCBD-monovalinate-dihemisuccinate in an acceptable base or carrier.

The present invention can also encompass a method of preventingaddiction to morphine because of extended morphine use comprisingadministering to a subject in need of such treatment an effective amountof at least one compound per formula I or preferably the compound usedin this method is at least one compound wherein the compound isCBD-Di-Glutaminate, CBD-Di-Hemisuccinate, CBD-Di-Alaninate Ester,CBD-Di-Alaninate-Di-Hemisuccinate, CBD-Di-Valinate,CBD-Di-Valinate-Di-HS, CBD-Di-Hemiglutarate, CBD-Mono-Valinate,CBD-Mono-Valinate-Mono-Hemisuccinate, orCBD-monovalinate-dihemisuccinate in an acceptable base or carrier.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows plasma levels of CBD vs time following rectaladministration of 6.125 mg or 4.625 mg CBD-Val-HS in a lipophilicsuppository (Wecobe W base).

FIG. 2 shows the plasma levels of CBD following the rectaladministration of 7 mg CBD-Val-HS in a hydrophilic base (PEG 1000).

FIG. 3 shows plasma levels of CBD-Mono-VHS vs. time following rectaladministration of 7.5 mg CBD-Mono-VHS in a lipophilic suppository(Wecobe W base).

FIG. 4 shows plasma levels of CBD-Mono-VHS vs. time following rectaladministration of 7.5 mg CBD-Mono-VHS in a hydrophilic suppository (PEG1000 base).

FIG. 5 shows plasma levels of CBD-Mono-VHS vs. time following oraladministration of 4 mg CBD-Mono-VHS in sesame seed oil.

FIG. 6a shows organ levels of CBD-Mono-VHS in 2 and 4 hr. post oraladministration of 4 mg CBD-Mono-VHS.

FIG. 6b shows plasma levels of CBD-Mono-VHS in 2 and 4 hr. post oraladministration of 4 mg CBD-Mono-VHS.

FIG. 7a shows concentration of CBD and THC vs. time post incubation ofCBD at 37° C. at pH 1.2.

FIG. 7b shows concentration of CBD vs. time post incubation of CBD at37° C. at pH 7.4.

FIG. 8 shows concentration of CBD-Mono-VHS vs. time at pH's of 1.2 and7.4.

FIG. 9 shows concentration of CBD-Di-VHS post incubation at 37° C. vs.time at pHs of 1.2 and 7.4.

FIG. 10 shows plasma levels of CBD vs. time following rectaladministration of 7.5 mg CBD-HG in a lipophilic suppository (Wecobe Wbase).

FIGS. 11a-d show organ levels of CBD and CBD-Mono-VHS 70 minutes afterIP administration of two doses (30 and 60 μg) of CBD-Mono-VHS in mice:a) liver levels, b) spleen levels, c) kidney levels, and d) brainlevels.

FIG. 12 shows plasma concentration of CBD-Mono-VHS 70 minutes after IPadministration of two doses (30 and 60 μg) of CBD-Mono-VHS in mice.

FIG. 13 shows mean paw withdrawal in grams of force (+/−SEM). Dashedlines depict baseline responses pre- and post-cisplatin administrationprotocol prior to drug efficacy screening. Vertical bars represent meanresponses on drug CBD-Val-HS efficacy screening day. Doses are in mg/kgand delivered IP 45 minutes prior to testing. * denotes significantattenuation of tactile allodynia compared to the vehicle group (p<0.05).Sample sizes were n=5-14.

FIG. 14 shows mean paw withdrawal in grams of force (+/−SEM). Dashedlines depict baseline responses pre- and post-cisplatin administrationprotocol prior to drug efficacy screening. Vertical bars represent meanresponses on drug CBD-Val-HS efficacy screening day. Doses are in mg/kgand delivered IP 45 minutes prior to testing. * denotes significantattenuation of tactile allodynia compared to the vehicle group (p<0.05).Sample sizes were n=9-11.

FIG. 15 shows the effects of CBD and CBD-val-HS on morphine placepreference scores. Values represent difference in the mean ratio of time(seconds) spent in the S+(drug-paired) chamber during pre- andpost-condition trials. Open bars reflect saline treated animals andstriped bars represent morphine treated animals. *denotes significantdifference form the vehicle group. † denotes significant attenuation ofmorphine preference. Sample sizes were n=7-10.

CBD-AMINO ACID ESTER SYNTHESIS Example 1: Synthesis ofCBD-Di-Glutaminate

A. Synthesis of CBD-Diglutaminate-Boc (CBD-Di-Gln-Boc)

CBD was dissolved in DCM and catalytic amount of DMAP was added to itwhile stirring. Boc-glutamine (2.2 eq.) was dissolved in DCM and 2.2 eq.of DCC was added to it while stirring. CBD/DMAP solution was added toBoc-glutamine/DCC solution and allowed to stir for 30 minutes. Thinlayer chromatography (10% EtOAc/90% Hexane) indicated the completion ofreaction. The product was purified using silica gel and product waseluted (in 90% EtOAc/10% Hexane) as pure compound.

B. Deprotection of CBD-Di-Gln-Boc to CBD-Di-Gln

CBD-di-Gln-boc was dissolved in THF while stirring. HCl_((g)) wasbubbled through it for approximately 3 minutes while stirring. ExcessHCl_((g)) was removed with N_(2(g)) and the solvent was evaporated.Product was confirmed by mass spectrometry.

Example 2: Synthesis of CBD-Di-Hemisuccinate

CBD was dissolved in DCM and catalytic amount of DMAP was added to itwhile stirring. Succinic anhydride (2.2 eq.) and triethylamine wereadded to CBD/DMAP solution. The reaction was stirred for 30 minutes. Theproduct was purified using silica gel and eluted (in a gradientbeginning at 0% EtOAc/100% Hexane and increasing to 75% EtOAc/25%Hexane) as pure compound. Product was confirmed by mass spectrometry.

Example 3: Synthesis of CBD-Di-Alaninate Ester

A. Synthesis of CBD-Di-Ala-Boc

CBD was dissolved in DCM and catalytic amount of DMAP was added to itwhile stirring. Boc-alanine (2.2 eq.) was dissolved in DCM and 2.2 eq.of DCC was added to it while stirring. CBD/DMAP solution was added toBoc-alanine/DCC solution and allowed to stir for 30 minutes. Thin layerchromatography (10% EtOAc/90% Hexane; R_(f)=0.15) indicated thecompletion of reaction.

The product was purified using silica gel and product was eluted (in agradient beginning at 0% EtOAc/100% Hexane and increasing to 15%EtOAc/85% Hexane) as pure compound.

B. Deprotection of CBD-Di-Ala-Boc to CBD-Di-Ala

CBD-di-Ala-boc was dissolved in THF while stirring. HCl_((g)) wasbubbled through it for approximately 3 minutes while stirring. ExcessHCl_((g)) was removed with N_(2(g)) and the solvent was evaporated todryness. Product was confirmed by mass spectrometry.

Example 4: Synthesis of CBD-Di-Alaninate-Di-Hemisuccinate

CBD-Di-Ala was dissolved in DCM and catalytic amount of DMAP was addedto it while stirring. Succinic anhydride (2.2 eq.) and triethylaminewere added to CBD-Di-Ala/DMAP solution. The reaction was stirredovernight. The product was purified using silica gel and eluted (in agradient beginning at 30% EtOAc/70% Hexane and increasing to 100%EtOAc/0% Hexane) as pure compound. Product was confirmed by massspectrometry.

Example 5: Synthesis of CBD-Di-Valinate

A. Synthesis of CBD-Di-Val-Boc

CBD was dissolved in DCM and catalytic amount of DMAP was added to itwhile stirring. Boc-valine (2.2 eq.) was dissolved in DCM and 2.2 eq. ofDCC was added to it while stirring. CBD/DMAP solution was added toBoc-valine/DCC solution and allowed to stir for 5 minutes. Thin layerchromatography (10% EtOAc/90% Hexane) indicated the completion ofreaction. The product was purified using silica gel and product waseluted (in a gradient beginning at 0% EtOAc/100% Hexane and increasingto 5% EtOAc/95% Hexane) as pure compound.

B. Deprotection of CBD-Di-Val-Boc to CBD-Di-Val

CBD-di-Val-boc was dissolved in THF while stirring. HCl_((g)) wasbubbled through it for approximately 3 minutes while stirring. Excess ofHCl_((g)) was removed with N_(2(g)). Product was confirmed by massspectrometry.

Example 6: Synthesis of CBD-Di-Valinate-Di-HS

CBD-Di-Val was dissolved in DCM and catalytic amount of DMAP was addedto it while stirring. Succinic anhydride (2.2 eq.) and triethylaminewere added to CBD-Di-Val/DMAP solution. The reaction was stirredovernight. The product was purified using silica gel and eluted (in agradient beginning at 0% EtOAc/100% Hexane and increasing to 80%EtOAc/20% Hexane) as pure compound. Product was confirmed by massspectrometry.

Example 7: Synthesis of CBD-Di-Hemiglutarate

CBD was dissolved in DCM and catalytic amount of DMAP was added to itwhile stirring. Glutaric anhydride (2.2 eq.) and triethylamine wereadded to CBD/DMAP solution. The reaction was stirred for 30 minutes. Theproduct was purified using silica gel and eluted (in a gradientbeginning at 0% EtOAc/100% Hexane and increasing to 40% EtOAc/60%Hexane) as pure compound. Product was confirmed by mass spectrometry.

Example 8: Synthesis of CBD-Mono-Valinate

A. Synthesis of CBD-Mono-Val-Boc

CBD was dissolved in DCM and catalytic amount of DMAP was added to itwhile stirring. Boc-valine (1.1 eq.) was dissolved in DCM and 1.1 eq. ofDCC was added to it while stirring. CBD/DMAP solution was added toBoc-valine/DCC solution and allowed to stir for 5 minutes. Thin layerchromatography (10% EtOAc/90% Hexane) indicated the completion ofreaction. The product was purified using silica gel and product waseluted (in a gradient beginning at 0% EtOAc/100% Hexane and increasingto 3% EtOAc/97% Hexane) as pure compound.

B. Deprotection of CBD-Mono-Val-Boc to CBD-Mono-Val

CBD-Mono-Val-boc was dissolved in THF while stirring. HCl_((g)) wasbubbled through it for approximately 2 minutes while stirring. ExcessHCl_((g)) was removed with N_(2(g)). Product was confirmed by massspectrometry.

Example 9: Synthesis of CBD-Mono-Valinate-Mono-Hemisuccinate

Structure of CBD-Mono-Valinate-Mono-Hemisuccinate(CBD-Mono-Val-Mono-HS).

C. Synthesis of CBD-Mono-Val-HS

CBD-Mono-Val was dissolved in DCM and catalytic amount of DMAP was addedto it while stirring. Succinic anhydride (1.1 eq.) and triethylaminewere added to CBD-Mono-Val/DMAP solution. The reaction was stirredovernight. The product was purified using silica gel and eluted (in agradient beginning at 0% EtOAc/100% Hexane and increasing to 30%EtOAc/70% Hexane) as pure compound. Product was confirmed by massspectrometry.

Example 10: Synthesis of CBD-Monovalinate-Dihemisuccinate(CBD-Mono-Val-Di-HS) Synthesis of CBD-Mono-Val-Boc

CBD was dissolved in DCM and catalytic amount of DMAP was added to itwhile stirring. Boc-valine (1.1 eq.) was dissolved in DCM and 1.1 eq. ofDCC was added to it while stirring. CBD/DMAP solution was added toBoc-valine/DCC solution and allowed to stir for 5 minutes. Thin layerchromatography (10% EtOAc/90% Hexane) indicated the completion ofreaction. The product was purified using silica gel and product waseluted (in a gradient beginning at 0% EtOAc/100% Hexane and increasingto 3% EtOAc/97% Hexane) as pure compound.

B. Deprotection of CBD-Mono-Val-Boc to CBD-Mono-Val

CBD-Mono-Val-boc was dissolved in THF while stirring. HCl_((g)) wasbubbled through it for approximately 2 minutes while stirring. ExcessHCl_((g)) was removed with N_(2(g)). Product was confirmed by massspectrometry.

C. Synthesis of CBD-Mono-Val-diHS

CBD-Mono-Val was dissolved in DCM and catalytic amount of DMAP was addedto it while stirring. Succinic anhydride (2.2 eq.) and triethylaminewere added to CBD-Mono-Val/DMAP solution. The reaction was stirredovernight. The product was purified using silica gel and eluted (in agradient beginning at 0% EtOAc/100% Hexane and increasing to 30%EtOAc/70% Hexane) as pure compound. Product was confirmed by massspectrometry.

Example 11: Preparation of Topical Ophthalmic Formulations ofBiologically Active CBD Analogs

Formulations: 0.5% w/v CBD equivalent in Tocrisolve emulsion.Tocrisolve composition: W/O emulsion composed of a 1:4 ratio of soyaoil/water that is emulsified with the block co-polymer Pluronic F68.Manufacturing process for the Tocrisolve emulsion:

-   -   Add accurately weighed amount of drug a glass vial.    -   Add required volume of Torcisolve blank emulsion to each vial    -   Vortex each vial for 5 minutes.    -   Sonicate each vial for 10 minutes.    -   Centrifuge each vial for 5 minutes at 9000 rpm at 25° C.    -   Collect the supernatant and analyze for CBD, CBD-Val Mono and        CBD-Val-HS mono as applicable.        Table 1 shows the solubility of CBD and CBD analogs in        Tocrisolve emulsion.

TABLE 1 Solubility of CBD and its analogs in Tocrisolve ® emulsion.CBD-VAL-MONO CBD-VAL-HS-MONO CBD-HS CBD-VAL-HCl CBD-VAL-HS (In terms (Interms (In terms (In terms (In terms CBD of CBD) of CBD) of CBD) of CBD)of CBD) Maximum solubility 1.19 1.41 1.18 1.12 2.04 1.21 achieved in(1.07) (0.61) (0.7) (1.09) (0.53) Tocrisolve (% w/v)

Example 12: In Vivo Eye Tissue Levels of CBD and CBD Analogs 90 Min.After Topical Application of 50 μL of Formulations Containing theEquivalent of 250 μg of CBD in Tocrisolve® Emulsion

Conscious male New Zeland albino rabbits were used. The formulationswere applied topically into the rabbits eyes (50 μL containing theequivalent of 250 μg CBD) in Tocrisolve® emulsion formulations asdescribed in Example 11. The animals were sacrificed 90 min. after drugapplication and the eye tissues harvested for analysis.

Table 2 shows the tissue levels (ng/g) following administration of CBD,CBD-Val-HCl and CBD-Val-HS.

The data showed that, while CBD and the water soluble CBD-Val-HCl onlyshowed very low levels in the retina choroid, the CBD-Val-HS reached alltissues in high concentrations.

TABLE 2 Ocular tissue concentrations of CBD, CBD-Val and CBD-Val-HS(ng/gm of tissue); 90 min post topical application of CBD (0.47%), CBD-Val-HCl (0.94%) or CBD-Val-HS (1.2%) in Tocrisolve ® emulsion (Dose: 250μg CBD; 50 μL instilled volume) respectively. Concentration (ng/gm oftissue); Dose in terms of CBD equivalent: 0.5% w/v & 50 μL: 250 μg 0.94%w/v 1.2% w/v 0.5% w/v CBD-Val-HCl CBD-Val-HS CBD CBD- CBD- CBD-Val-Tissue CBD CBD Val CBD Val HS Retina 17.3 ± 6.5 ND 9.1 ± 1.5 ND ND 417 ±114 Choroid Aqueous ND ND ND ND ND 24.6 ± 16.2 Humor Vitreous ND ND NDND ND 612 ± 264 Humor ND-below detection limit.

Example 13: In Vivo Eye Tissue Levels of CBD VS Other Analogs of CBD

The same procedure was followed as shown under Example 12. AdditionalCBD analogs were tested in this example. In this example the tissuelevels of both free CBD and intact analog were determined. Results areshown in Table 3.

Formulations: Fifty microlitres of 0.5% w/v CBD in Tocrisolve emulsion(Dose: 0.25 mg)Animal model: Conscious male new Zealand albino rabbits, Duration of thestudy: 90 min.

TABLE 3 Ocular tissue levels of both CBD and its analogs 90 min.following topical administration of the different analogs inTocrisolve ® emulsion. CBD-VAL-MONO CBD-VAL-HS-MONO 0.65% w/v in CBDCBD-HS 0.97% w/v in Tocrisolve 0.53% w/v in 0.81% w/v in Tocrisolveemulsion Tocrisolve Tocrisolve emulsion Set 1 CBD Conc. emulsionemulsion Analog Conc. CBD Conc. Analog Conc. detected CBD Conc. AnalogConc. CBD Conc. (ng/g of (ng/g of (ng/g of (ng/g of (ng/g of (ng/g of(ng/g of tissue) tissue) tissue) tissue) tissue) tissue) tissue) AQ 90.3± 13.6 ND ND ND ND ND ND Humor Vitr. ND ND ND ND ND ND ND Humor Retina689 ± 127 194 ± 31.2 ND ND ND ND 263 ± 132 Choroid Iris 1034 ± 87.4  353± 43  ND ND ND ND 267 ± 46  Ciliary Bodies

The data showed that while CBD and the free amino acid analogs showed nolevels in the tissues at all, CBD-Val-HS reached both retina choroid andthe iris-ciliary bodies but showed no detectable levels of CBD. On theother hand, CBD-mono-Val-HS was detected in high concentration in theaqueous humor, retina choroid and iris-ciliary bodies. Furthermore, theCBD-mono-Val-HS showed high levels of Free CBD in the retina choroid andiris-ciliary bodies.

Example 14: Comparison of the CBD and CBD-Analog Levels in the OccularTissues Following Topical Administration of the Two Biologically ActiveAnalogs, Namely CBD-Di-Val-HS and CBD-Mono-Val-HS

This example is a repeat of the experiment performed under Example 13 toshow results reproducibility.

Sample Preparation:

Aqueous humor, Vitreous humor, Retina-Choroid and Iris-Ciliary bodiesanalysed for parent compound as well as CBD.

Formulations: Fifty microlitres of 0.5% w/v Tocrisolve emulsionformulations (Dose: 0.25 mg)

Animal model: Conscious male new Zealand albino rabbits, Duration of thestudy: 90 min

TABLE 4 Ocular tissue concentrations of CBD and CBD analogs 90 min posttopical application of CBD-Val-HS-Mono or CBD- VAL-HS in Tocrisolve ®emulsion (Dose: 250 μg; 50 μL instilled volume) respectively. AH—aqueoushumor, VH—Vitreous humor, RC—Retina-choroid, IC—Iris Ciliary bodies.ND—below detection limit. 0.97% w/v in Tocrisolve emulsionCBD-VAL-HS-MONO 1.2% CBD-VAL-HS Set 2 Set 2 Analog CBD Analog CBDConcen- concen- Concen- concen- tration tration tration tration (ng/g of(ng/g of (ng/g of (ng/g of tissue) tissue) tissue) tissue) Aqueous 98.7± 19.8 61.3 ± 5.9  ND ND Humor Vitreous ND ND ND ND Humor Retina 519 ±476 503 ± 373 142 ± 76 ND Choroid Iris 422 ± 197 585 ± 103  ND* NDCiliary Bodies Plasma ND ND ND ND *Only one of the animals showed 160 ngof CBD-Val-HS/g of tissue. The analog was below quantifiable levels inthe other animals.

The data in Table 4 show similar results to those shown in Example 13and prove that CBD-Mono-Val-HS is a superior analog for penetration intothe different tissues of the eye. When biologically active analogs aredesigned such that R1 and R2 are natural amino acid residues (e.g.CBD-di-Val) or a dicarboxylic acid (e.g. CBD-di-HS) esters or the esterof the amino acid amide with a dicarboxylic acid (e.g.CBD-di-Val-di-HS), penetration into the ocular tissues is not adequate.

Only when the analog is a mono amino acid ester with the nitrogen of theamino acid in an amide linkage with a dicarboxylic acid, was the desiredpenetration to the inner chambers of the eye achieved.

Example 15: Bioavailability of CBD from Suppository FormulationsContaining CBD-Di-Val-Di-HS (CBD-Val-HS)

CBD-Val-HS was formulated in both lipophilic (Wecobe W base) andhydrophilic (PEG 1000 base) suppository formulations. The formulationswere administered to cannulated rats (100 mg suppository per rat) andblood samples were collected, centrifuged and the plasma separated forLC/MS/MS analysis. The amount of CBD in the plasma samples wasquantified. The amount of CBD-Val-HS in the plasma samples was notquantified.

FIG. 1 shows the plasma levels of CBD vs. time following administrationof 6.125 mg or 4.625 mg CBD-Val-HS in a lipophilic suppository (Wecobe Wbase).

FIG. 2 shows the plasma levels of CBD following the administration of 7mg CBD-Val-HS in a hydrophilic base (PEG 1000).

Higher levels of CBD were achieved from a hydrophilic base containingCBD-Va-HS that when the same analog was delivered via a lipophilic base.

Example 16: Bioavailability of CBD-Mono-Val-Mono-Hemisuccinate(CBD-Mono-VHS) from a Lipophilic Suppository Formulation (Wecobee M)

CBD-Mono-Val-Mono-HS was formulated in Wecobee M suppository base (atriglyceride lipophilic base) at 75 mg/mL of melted base. The study wascarried out in a cannulated rat model. Three animals were administered100 μl. each of the semisolid formulation for a rectal dose of 7.5 mgCBD-Mono-VHS. This is followed by collection of blood samples (250 μl.)at each data point (0, 0.25, 0.5, 1, 2, 4, 6, and 24 hr.). The blood wascentrifuged and the plasma was used for LC-MS/MS analysis. The resultsare shown in Table 5 and FIG. 3.

TABLE 5 Plasma Concentration of CBD-Mono-VHS for Individual Animals overTime Post Administration of 7.5 mg of the Drug in a Lipophilic (WecobeeM) Suppository Form in Rats Time (Hrs.) 0 0.25 0.5 1 2 4 6 24 Animal 10.0 3.9 12.8 13.8 14.5 27.5 41.6 N/A Animal 2 0.0 7.1 11.6 18.5 34.645.1 53.0 44.3 Animal 3 0.0 7.1 9.0 14.1 12.7 22.0 24.8 7.3 Average 0.06.0 11.1 15.5 20.6 31.5 39.8 17.2

Example 17: Bioavailability of CBD-Mono-Val-Mono-Hemisuccinate(CBD-Mono-VHS) from a Hydrophilic Suppository Formulation (PolyethyleneGlycol 1000, PEG 1000)

CBD-Mono-Val-Mono-HS was formulated in PEG 1000 suppository base (ahydrophilic suppository base) at 75 mg/mL of melted base. The study wascarried out in a cannulated rat model. Three animals were administered100 μl. each of the semisolid formulation for a rectal dose of 7.5 mgCBD-Mono-VHS. This is followed by collection of blood samples (250 μl.)at each data point (0, 0.25, 0.5, 1, 2, 4, 6, and 24 hr.). The blood wascentrifuged and the plasma was used for LC-MS/MS analysis. The resultsare shown in Table 6 and FIG. 4.

TABLE 6 Plasma Concentration of CBD-Mono-VHS for Individual Animals overTime Post Administration of 7.5 mg of the Drug in a Hydrophilic (PEG1000) Suppository Form in Rats Time (Hrs.) 0 0.25 0.5 1 2 4 6 8 24Animal 1 0.0 10.1 38.4 54.3 123.0 60.5 37.4 21.6 2.5 Animal 2 0.0 14.832.9 108.0 113.0 53.5 30.1 27.3 2.6 Animal 3 0.0 14.7 44.2 106.0 108.057.5 18.6 44.8 0.0 Average 0.0 13.2 38.5 89.4 114.7 57.2 28.7 24.0 0.9

Example 18. Oral Bioavailability of CBD-Mono-Val-Mono-Hemisuccinate(CBD-Mono-VHS)

CBD-Mono-VHS was formulated in a sesame seed oil (Welch, Holme and ClarkCo. lot #39375) formulation composed of 40 mg/mL solution of the drugsubstance/ml. Animals (cannulated rats, n=4) were dosed 100 μl of theoil solution by oral gavage. Blood samples were collected at 0, 0.25,0.5, 1, 2, 4, 6, 8, and 24 hr. after dosing. The blood samples werecentrifuged and the plasma was analyzed for CBD-Mono-VHS. Table 7 andFIG. 5 show the results, with very high blood levels which remainsignificant (>10 ng/mL) at 24 hr. after dosing.

TABLE 7 Plasma Concentration of CBD-Mono-VHS for Individual Animals PostOral Administration of a 4 mg/animal Dose of the Drug Time (Hrs.) 0 0.250.5 1 2 4 6 8 24 Animal 1 0.0 1512.3 2655.0 3120.9 1317.3 423.3 181.089.8 37.8 Animal 2 0.0 370.2 1437.1 2496.6 399.5 116.1 397.8 210.0 47.1Animal 3 0.0 978.0 1238.2 1492.0 264.8 284.8 197.8 264.4 17.5 Animal 40.0 1255.5 1174.8 1400.6 392.2 115.1 71.4 44.6 6.5 Average 0.0 1029.01626.3 2127.5 593.5 234.8 212.0 152.2 27.2

Example 19. Organ Distribution of CBD-Mono-VHS after Oral Administration

To determine whether CBD-Mono-VHS reaches the organs and especially thebrain, two cannulated rats were administered same dose as those inExample 18. One rat was sacrificed at 2 hr. after dosing and the otherat 4 hr. after dosing and the organs were harvested (brain, liver, andspleen) as well as blood for analysis. Table 8a shows the organ levelsof CBD-Mono-VHS at 2 and 4 hrs. after oral dosing (4 mg/animal) whileTable 8b shows the plasma levels.

The data are depicted in FIGS. 6a and 6 b.

The plasma levels were consistent with the data from Example 18 and theorgans showed high levels of the drug indicating effectivebioavailability.

TABLE 8a Organ levels of CBD-Mono-VHS at 2 and 4 hr. after oral dosingwith 4 mg/animal. CBD-Mono-Val-Mono-HS Time Organ Conc. (ng/organ) 2 HRBRAIN 556 LIVER 66484 KIDNEY 353 SPLEEN 1438 4 HR BRAIN 205 LIVER 8301KIDNEY 115 SPLEEN 392

TABLE 8b Plasma levels at 2 and 4 hr. after oral dosing with 4 mg/animalof CBD-Mono-VHS. CBD-Mono-Val-Mono-HS (Plasma) Time Conc. (ng/mL) 2 HR285 4 HR 53

Example 20. Stability of CBD-Mono-Val-Mono-Hemisuccinate (CBD-Mono-VHS)in Simulated Gastric Juice and Intestinal Juice

CBD is known to convert, at least partially, to Δ⁹-THC (the psychoactivecomponent of cannabis) and to other cannabinoids under the acidicconditions of the stomach. (Watanabe, K., Itokawa, Y., Yamaori, S.,Funahashi, T., Kimura, T., Kaji, T., Usami, N., Yamamoto, I., 2007;Conversion of cannabidiol to Δ⁹-tetrahydrocannabinol and relatedcannabinoids in artificial gastric juice, and their pharmalogicaleffects in mice, Forensic Toxicol, 25, 16-21. and Merrick, J., Lane, B.,Sebree, T., Yaksh, T., O'Neill, C., Banks, S., 2016; Identification ofPsychoactive Degradants of Cannabidiol in Simulated Gastric andPhysiological Fluid, Cannabis and Cannabinoid Research, 1.1, 102-112).This results in side effects that are proportional to the degree ofconversion.

The stability CBD and CBD analogs (CBD-Mono-VHS and CBD-Di-VHS) wasevaluated under acidic and alkaline conditions to simulate exposure togastric and intestinal fluids. The procedure is outlined as follows:

-   -   1. Stock solution of 5 mg/mL CBD, CBD-Mono-Val-Mono HS,        CBD-Di-Val-Di HS was prepared.    -   2. Simulated Gastric Fluid (pH 1.2)+1% (SDS) was prepared and        kept in 37° C. water bath.    -   3. Physiological buffer (pH 7.4)+1% SDS was prepared and kept in        37° C. water bath.    -   4. 100 μL of CBD, CBD-Mono-Val-Mono HS or CBD-Di-Val-Di-HS stock        in acetonitrile (equivalent to 500 μg) was spiked into separate        vials containing 5 ml of either pH 1.2 and 7.4.    -   5. At each time point, 100 μL of the solution was withdrawn.    -   6. 900 μL acetonitrile was added to each sample.    -   7. All samples centrifuged at 4° C. and 13,000 rpm.    -   8. 100 μL of the supernatant was withdrawn; to this 100 μL of        supernatant, 900 μL of acetonitrile was added and placed in LC        vials for analysis. Tables 9, 10 and 11, and FIGS. 7a, 7b , 18,        and 19 show the results.

CBD converts to Δ⁹-THC under acidic conditions while CBD analogs of thisinvention do not produce Δ⁹-THC.

TABLE 9 Concentration (ng/ml) of CBD and Δ⁹-THC, at different incubationtimes at 37° C. and at pH's of 1.2 and 7.4 Acid (pH 1.2) Base (pH 7.4)CBD Δ⁹-THC CBD Time Peak Peak Time Peak Point Area Conc. Area Conc.Point Area Conc. 0 1578900 656 70146 38 0 1816000 760 15 1343400 553433990 238 15 2233800 943 30 546430 204 442900 243 30 2397500 1015 60335800 111 904900 496 60 263670 1119 90 288960 91 1141200 625 90 25498001081 120 186660 46 829150 454 120 2307100 975 Conclusion: CBD ispartially converted to THC under the acidic conditions of the gastricjuice, but stable under the physiologic pH of 7.4.

TABLE 10 Concentration (ng/ml) of CBD-Mono-Val-Mono-HS at different timepoints post incubation at pH's of 1.2 and 7.4 at 37° C. Acid (pH 1.2)Base (pH 7.4) CBD-Mono-Val- CBD-Mono-Val- Mono-HS Mono-HS Time PointPeak Area Conc. Time Point Peak Area Conc. 0 1515300 941 0 1424000 88615 2246500 1380 15 2345100 1439 30 2400300 1472 30 1941900 1197 602579800 1579 60 2932900 1791 90 2411300 1478 90 2639800 1615 120 24795001519 120 2833100 1731

TABLE 11 Concentration (ng/ml) of CBD-Di-Val-Di-HS at different timepoints post incubation at pH's of 1.2 and 7.4 at 37° C. Acid (pH 1.2)Base (pH 7.4) CBD-Di-Val-Di-HS CBD-Di-Val-Di-HS Time Point Peak AreaConc. Time Point Peak Area Conc. 0 454560 754 0 488890 794 15 13468001797 15 549120 865 30 1091200 1498 30 776690 1131 60 1418400 1881 601004900 1397 90 1403700 1863 90 994740 1386 120 1420400 1883 120 8557101223

Example 21. Bioavailability of CBD from Suppository FormulationsContaining CBD-Hemiglutarate (CBD-HG)

CBD-Hemiglutarate was formulated in a lipophilic suppository base(Wecobee M) at 75 mg/mL of molten base. Doses of 100 μl. of theformulation were administered rectally (equivalent to 7.5 mgdose/animal) to cannulated rats (n=4). Blood samples (0.25 mL) werecollected at 0, 0.25, 0.5, 1, 2, 4, 6, 8, and 24 hr. after dosing. Aftercentrifugation of the blood, plasma was collected (100 μl.) andsubjected to LC-MS/MS analysis for CBD. The amount of CBD-HG in theplasma was not determined. Table 12 and FIG. 10 show the results.

TABLE 12 Plasma Concentration of CBD Following Rectal Administration ofCBD-Hemiglutarate (7.5 mg dose) in a Lipophilic Suppository FormulationTime (Hrs.) 0 0.25 0.5 1 2 4 6 8 24 Animal 1 0 27.8 29 5.92 18.8 15.8 00 0 Animal 2 0 0 42.3 8.65 0 7.45 0 0 0 Animal 3 0 0 44.3 17 16.8 6.63 00 0 Animal 4 0 14.5 6.16 11.5 26.2 7.43 0 0 0 Average 0 10.575 30.4410.7675 15.45 9.3275 0 0 0

Example 22. Plasma and Organ Concentrations of CBD and CBD-Mono-VHSFollowing IP Administration of CBD-Mono-VHS in Mice

CBD-Mono-VHS was administered intraperitoneally to mice at 2 doses (30μg and 60 μg equivalent of CBD/mouse). Seventy minutes after dosing theanimals (3 mice in each dose group), all animals were sacrificed. Blood,as well as organs (liver, spleen, kidney, and brain), were harvested forLC-MS/MS analysis of their content of both CBD and CBD-Mono-VHS.

Table 13 shows the total CBD-Mono-VHS content of each organ for eachanimal for both doses with average and standard deviation, while Table14 shows the total CBD content. Also shown is the concentration ofCBD-Mono-VHS in the plasma 70 minutes after dosing.

The results are also depicted in FIG. 11a (liver), FIG. 11b (spleen),FIG. 11c (kidney), FIG. 11d (brain), and FIG. 12 (plasma concentration(ng/mL)) for individual animals from each dose.

Conclusion: IP administration of CBD-Mono-VHS in mice results in highconcentrations of the drug in all organs tested in a dose proportionalmanner. More importantly, the compound crosses the blood brain barrier,a significant finding in the use of this compound for the treatment ofCNS based disease conditions.

TABLE 13 Total Drug Load (in ng) of CBD-Mono-Val-Mono-HS in theDifferent Organs and the Plasma Concentrations (ng/mL) 70 Minutes PostIP Administration of Two Dose Levels (30 and 60 μg./animal) of the DrugTotal CBD-Mono-Val-Mono-HS (ng)* Animal Dose # Liver Kidney Spleen BrainPlasma Total Low 1 1543.96 132.55 150.36 5.81 22.97 1855.656 Dose 21431.98 88.05 105.24 13.48 32.08 1670.831 (30 μg 3 534.11 84.14 283.028.26 32.24 941.765 CBD/ AVG. 1170.01 101.58 179.54 9.18 29.10 1489.42mouse) SD 553.55 26.89 92.41 3.92 5.31 483.20 High 4 8380.90 780.57711.31 46.59 137.82 10057.18 Dose 5 2882.40 248.34 477.40 42.45 100.533751.113 (60 μg 6 11413.38 2552.93 1126.58 101.50 393.00 15587.4 CBD/AVG. 7558.89 1193.95 771.76 63.51 210.45 9798.56 mouse) SD 4324.4891206.627 328.787 32.96302 159.1886 5922.379 *The organ levels are totalcontent of CBD-Mono-VHS in the entire organ while the plasma content isin ng/ml.

TABLE 14 Total Drug Load (in ng) of CBD in the Different Organs and thePlasma Concentrations (ng/mL) 70 Minutes Post IP Administration of TwoDose Levels (30 and 60 μg/animal) of the Drug Total CBD (ng) Animal Dose# Liver Kidney Spleen Brain Plasma Total Low 1 81.42 0.00 0.00 0.00 0.0081.42 Dose 2 41.82 7.03 10.04 0.00 0.00 58.89 (30 μg 3 19.61 0.00 18.350.00 0.00 37.96 CBD/ AVG. 47.62 2.343 9.46 0.00 0.00 59.42 mouse) SD25.56 3.31 7.50 0.00 0.00 21.73 High 4 319.91 18.50 93.63 0.00 0.00432.04 Dose 5 195.66 14.96 99.63 0.00 0.00 310.25 (60 μg 6 369.75 0.000.00 2.86 0.00 372.61 CBD/ AVG. 295.11 11.15 64.42 0.95 0.00 371.63mouse) SD 73.20 8.02 45.62 1.35 0.00 60.90

In a further embodiment of the present invention the inventors exploredwhether cannabidiol (CBD) or biologically active CBD analogs possessedanalgesic properties alone and in combination of a sub-analgesic dose ofor morphine in a mouse model of cisplatin induced neuropathy. Micereceived 12 alternating days of 2.3 mg/kg cisplatin and Ringers solutionIP. An electronic Von Frey quantified the development of tactileallodynia before, during and after the cisplatin protocol and served asthe endpoint for analgesic screening. Test articles given alone or incombination included, vehicle, morphine (0.5 and 2.5 mg/kg) and CBD (1.0and 2.0 mg/kg in Experiment 1) or a CBD analog (1.0-4.0 mg/kg inExperiment 2) and were given IP 45 m before testing. Six dosings ofcisplatin produced robust tactile allodynia that was attenuated by 2.5mg/kg morphine. CBD produced a modest attenuation of tactile allodyniathat was potentiated by sub-analgesic doses of morphine. Thebiologically active CBD analog produced a robust attenuation of tactileallodynia equivalent to morphine; this effect was reproduced at lowerdoses when given in combination of sub-analgesic doses of morphine.These findings suggest that a biologically active CBD analog may be aneffective pain management strategy for neuropathy associated withchemotherapy in oncology settings

Example 23: Efficacy of CBD in a Cisplatin-Induced Tactile AllodyniaModel Subjects

Male C57BL/6 mice (25-30 g; Envigo; Indianapolis, Ind.) were housed 5per polycarbonate tub with soft bedding in a temperature and humiditycontrolled vivarium. Mice were maintained under a 12-hour light/darkcycle with lights on at 06:00. Food and water were available ad libitum.Animals acclimated to the vivarium 1 week prior to experimentalmanipulations. All experimental procedures were approved by theInstitutional Animal Care and Use Committee at the University ofMississippi (Protocols 13-017 and 15-022).

Behavioral Measures

An electronic von Frey (eVF; Topcat Metrology Ltd; Little Downham, UK)quantified the development of tactile allodynia during CIN induction andserved as the endpoint in analgesic screening. Animals were placed intoan elevated clear Plexiglas enclosure (3.81×11.43×11.43 cm) with a metalrod floor. After an acclimation period of 15 min, a von Frey filamentwas applied to the mid plantar region of the hind paw and withdrawalthresholds were recorded. Filaments were applied to alternating left andright hind paws at 3 min intervals for a total of 4 measurements perpaw. The average score of these 8 tests served as the dependent measure.

Test Articles

Cisplatin (Tocris; Ellisville, Mo.) was dissolved in 0.9% saline toyield dosages 2.3 mg/kg/ml. Lactated Ringer's solution (0.25 mL; Abbottlaboratories; Chicago, Ill.) was used to hydrate mice to prevent kidneyand liver damage associated with repeated cisplatin administration.Morphine sulfate (Research Biochemicals International; Natick, Mass.)was dissolved in 0.9% saline to yield dosages of 0.1 and 2.5 mg/kg/ml.CBD 1.0 and 2.0 mg/kg/mL (ELI Laboratories; Oxford, Miss.) solutions,dissolved in 5% ethanol, 5% Cremophor and injectable water. All testarticles were administered intraperitoneally (IP).

Cisplatin Induction and Drug Efficacy Screening Procedure

Mice received 6 IP injections of cisplatin (2.3 mg/kg/mL) on alternatingdays with lactated Ringer's solution on intervening days over a 12-dayperiod. Baseline eVF measurements were taken prior to enrollment in thestudy to ensure balanced group assignments. To monitor the progressionof tactile allodynia additional eVF measurements were taken on RingersDay 3 and 6 prior to daily injections. On Ringers Day 6, eVFmeasurements revealed significantly lower paw withdrawal thresholdsindicative of neuropathy. Drug efficacy screening was conducted 2 dayslater to minimize the potential effect that repeated eVF testing mayhave on our CIN endpoint. Mice were counterbalanced and assigned to druggroups. All test compounds were delivered IP 45 minutes prior to eVFtesting.

Results and Discussion

The effects of the various test articles on cisplatin-induced tactileallodynia are summarized in FIG. 13. Baseline eVF responses prior to andafter cisplatin administration are shown as dashed lines. Following thecisplatin induction protocol, all mice showed lower response thresholdsindicative of tactile allodynia. A 1-way ANOVA of these data revealed asignificant decrease in paw withdrawal following the cisplatin protocol,F (1,71)=136.03, p<0.0001.

On drug efficacy screening day, vehicle-treated mice continued to showtactile allodynia. A sub-analgesic dose of morphine (0.1 mg/kg) did notaffect eVF responses whereas the 2.5 mg/kg morphine fully attenuatedtactile allodynia. CBD produced a modest attenuation of CIN at 1.0 butnot at the 2.0 mg/kg doses. The sub-analgesic dose of morphine given incombination with 2.0 mg/kg CBD attenuated tactile allodynia comparableto 2.5 mg/kg morphine. This CBD-opioid synergistic effect was notfurther enhanced with 2.5 mg/kg morphine.

A 1-way ANOVA of these data revealed a significant main effect for Drug,F (7,71)=15.72, p<0.0001. Fisher's LSD demonstrated that the meanwithdrawal thresholds were significantly higher than vehicle in 2.5mg/kg morphine, 1.0 mg/kg CBD, 0.1 mg/kg morphine in combination with1.0 and 2.0 mg/kg CBD, and 2.5 mg/kg morphine in combination with 2.0mg/kg CBD groups (ps≤0.0001).

These results demonstrate that a 6-dosing protocol of 2.3 mg/kgcisplatin over a 12-day period leads to robust tactile allodynia inmice, a hallmark sign of chemotherapy-induced neuropathy. Further,tactile allodynia persisted for several days after the last cisplatinadministration as evidenced by continued reduced paw withdrawalthresholds in vehicle-treated mice on drug efficacy screening day. Thesefindings are consistent with the literature that this and othercisplatin administration protocols produce CIN in rodents (Park et al.,2012; Guidon et al., 2012).

Mice receiving 2.5 mg/kg morphine displayed a robust attenuation oftactile allodynia. This finding is consistent with the literature thatopioid agonists produce analgesia in a wide variety of pain modelsincluding CIN (Guidon et al., 2012). Mice receiving 1.0 mg/kg CBDdisplayed a modest but significant attenuation of tactile allodynia. Ahigher dose of CBD was ineffective in the model. A sub-analgesic dose ofmorphine (0.1 mg/kg) did not further alter the anti-allodynic propertiesof 1.0 mg/kg CBD given alone. However, this sub-analgesic dose ofmorphine greatly enhanced the efficacy of 2.0 mg/kg CBD producing aneffect equivalent to that of 2.5 mg/kg dose of morphine alone. Finally,the effective morphine dose of 2.5 mg/kg did not further potentiate the2.0 mg/kg CBD. Collectively, these findings demonstrate that the modestefficacy of CBD can be greatly enhanced with sub-analgesic doses of anopioid agonist.

Example 24: Efficacy of CBD-Mono-VHS in a Cisplatin-Induced TactileAllodynia Model Methods

Subjects, behavior cisplatin injection protocol, and behavioral measureswere as described in Example 23. As before, morphine sulfate wasdissolved in 0.9% saline to yield dosages of 0.1 and 2.5 mg/kg/ml.Cannabidiol-mono-val-mono-hemisuccinate (CBD-Mono-VHS; ELI Laboratories;Oxford, Miss.) 1.0 to 4.0 mg/kg/mL was dissolved in 5% ethanol, 5%Cremophor and injectable water and are dose-equivalent in terms of CBDequivalent. The full doses of CBD-Mono-VHS were 1.6 to 6.4 mg/kg. Alltest articles were administered intraperitoneally (IP). All experimentalprocedures were approved by the Institutional Animal Care and UseCommittee at the University of Mississippi (Protocol 15-022).

Results and Discussion

Efficacy screening of these test articles on cisplatin-induced tactileallodynia are summarized in FIG. 14. Baseline eVF responses prior to andafter cisplatin administration are shown as dashed lines. Following thecisplatin induction protocol, all mice showed lower response thresholdsindicative of tactile allodynia. A 1-way ANOVA of these data revealed asignificant decrease in paw withdrawal following the cisplatin protocol,F (1,99)=601.36, p<0.0001.

On drug efficacy screening day, vehicle-treated mice continued to showtactile allodynia. A sub-analgesic dose of morphine (0.1 mg/kg) did notaffect eVF responses whereas the 2.5 mg/kg morphine fully attenuatedtactile allodynia. CBD-Mono-VHS given alone produced a dose-dependentattenuation of tactile allodynia that equal 2.5 mg/kg morphine at 3.0and 4.0 mg/kg. The combination of a sub-analgesic dose of morphine andCBD-Mono-VHS shifted this dose response curve to the left where 2.0mg/kg CBD-Mono-VHS attenuated tactile allodynia equal to that of 2.5mg/kg morphine.

Consistent with these findings, a 1-way ANOVA of these data revealed asignificant effect for Drug, F (10,99)=9.76, p<0.0001. Fisher's LSDdemonstrated that mean withdrawal thresholds were significantly highercompared to vehicle in 2.0-4.0 mg/kg CBD-Mono-VHS groups and drugcombination of 0.1 mg/kg morphine and 1.0-4.0 mg/kg CBD-Mono-VHS groups(ps≤0.0001).

These results are consistent with those of example 23 and show thiscisplatin administration protocol produces robust tactile allodynia inmice, a hallmark sign of chemotherapy-induced neuropathy. This tactileallodynia persisted for several days as evidenced by continued reducedpaw withdrawal thresholds in vehicle-treated mice on drug efficacyscreening day.

As in Example 23, mice receiving 2.5 mg/kg morphine displayed a robustattenuation of tactile allodynia. CBD-Mono-VHS produced a robust dosedependent attenuation of tactile allodynia equivalent to 2.5 mg/kgmorphine at the 3.0 and 4.0 mg/kg doses. Further, this CBD-Mono-VHS doseresponse function shifted to the left by the addition of a sub-analgesicdose of morphine. This drug combination achieved a maximum effect at the2.0 mg/kg CBD-Mono-VHS dose that was as efficacious as 2.5 mg/kgmorphine alone. Collectively, these findings demonstrate that the 1)CBD-Mono-VHS alone produces robust analgesia equal to opioids againstCIN and 2) these CBD-Mono-VHS effects can be achieved at lower doseswhen combined with sub-analgesic doses of an opioid agonist.

Example 25: Abuse Deterrent Effects of CBD and CBD-Val-HS in a Model ofAddiction Method Subjects

C57BL/6 male mice (25-30 g) were group housed (n=5) in a polycarbonatetub with soft bedding in a temperature and humidity controlled vivarium.Mice were maintained under a 12:12 hour light/dark cycle with lights onat 06:00. Food and water were available ad libitum. Mice acclimated tothe vivarium colony room one week prior to behavioral testing. Allexperimental procedures were approved on 18 May 2015 by theInstitutional Animal Care Committee at the University of Mississippi(Protocol #15-022).

Apparatus

Five place preference chambers (Model MED-CPP-3013; Med Associates, St.Albans, Vt.) were used for these experiments. Each chamber has twostimulus-distinct conditioning chambers (Black versus white coloredwalls and wire or mesh metal rod flooring; 16.75×12.70 cm) separated bya third central start chamber (7.25×12.70 cm; colored grey with a smoothsolid floor). Guillotine doors permitted confinement/access toindividual chambers.

Procedure

The groups in this study formed a 2×6 factorial design that combined 2levels of morphine and 6 levels of CBD and CBD-val-HS. Morphine Sulfate(Research Biomedical International; Natick, Mass.) was dissolved in 0.9%saline to yield a dosage of 2.5 mg/ml. Cannabidiol (>98% purity)solutions of 2.5, 5.0, 10.0, 20.0 mg/kg/mL and a single dose ofCBD-val-HS 10.0 mg/kg/mL (ELI Laboratories; Oxford, Miss.) weredissolved in 5% ethanol, 5% Cremophor, and injectable water. Micereceived dual IP administrations of test compounds.

Prior to behavioral testing, animals could acclimate to the testing roomfor at least 30 minutes. The CPP procedure consists of four phases: 1) a15-min apparatus habituation trial, 2) a 15-min trial to establishbaseline CPP scores, 3) six 45 min drug conditioning trials, and 4) a15-min trial to establish post-conditioning CPP score. During the drugfree habituation, baseline, and final preference trials animals wereplaced in the gray start chamber for a 5-minute adaption period.Following the adaption period the guillotine doors were lifted allowingaccess to the entire apparatus. The test apparatus was thoroughlycleaned with 70% ethanol solution after each trial.

CPP scores were determined by

$\frac{{Time}\mspace{14mu} {in}\mspace{14mu} {Black}}{{{Time}\mspace{14mu} {in}\mspace{14mu} {Black}} + {White}}$

and led to the establishment of the S+ chamber for drug conditioningwhereby S+ assigned to the non-preferred compartment. From these CPPscores, baseline and post-conditioning scores were calculated as

$\frac{{{Time}\mspace{14mu} {in}\mspace{14mu} S} +}{{{Time}\mspace{14mu} {in}\mspace{14mu} {S++}S} -}.$

Preference scores was calculated by taking subtracting post-conditioningand baseline CPP scores with positive values reflecting reward andnegative values reflecting aversion.

Statistical Analyses

Data were analyzed using SPSS software using two-way (between groups)ANOVA and one-way (between groups) ANOVA for simple effects analysesfollowed by planned comparisons (Fisher's LSD) for groups differenceswith significance at p<0.05.

Results

The effects of Cannabidiol and CBD-val-HS on Morphine conditioned placepreference scores are summarized in FIG. 15. Preference scores were nearzero in the control group (vehicle+saline) indicating there was littlechange in baseline and post-conditioning CPP scores. Morphine treatedanimals showed higher preference scores compared to the control group.Among the saline groups, CBD and CBD-val-HS did not show neither placepreference nor aversion. Among the Morphine groups, CBD dose-dependentlydecreased preference scores that approached significance at 10 mg/kgCBD. Further, CBD-val-HS at 10.0 mg/kg fully and significantly abolishedmorphine place preference.

A two-way ANOVA revealed a significant main effect for Morphine F(1,91)=24.57, p<0.001 and a significant main effect for Cannabidiol F(5,91)=2.843, p=0.021. The Cannabidiol x Morphine interaction was notsignificant F (5,91)=1.50, p=0.197. To determine whether morphinepossessed place preference, a one-way ANOVA of the Vehicle groups wereconducted and revealed a significant effect for Morphine F (1,15)=15.69,p<0.001. To test whether CBD possessed rewarding or aversive properties,a one-way ANOVA among the Saline groups found no significant treatmenteffect F (5,45)=1.311, p=0.276. To determine whether CBD attenuatedopioid reward, a one-way ANOVA on Morphine groups were performed andfound a significant treatment effect F (5,43)=2.984, p=0.021.

Planned comparisons among the morphine groups found preference scores inthe 10.0 mg/kg CBD approached significance (p=0.051) while CBD-val-HShad significantly lower preference scores than the CBD vehicle(p=0.005).

Conclusion

CBD-Mono-VHS significantly (P=0.005) blocked the addictive effects ofmorphine at 10 mg/kg while CBD at the same dose showed a tendency toblock the addictive effects of morphine (P=0.051).

BRIEF DESCRIPTION OF THE FORMULATIONS OF THE INVENTION

The formulations of the present invention comprise a therapeuticallyeffective amount of at least one biologically active cannabidiol analogcomposition of the formula wherein R1 is natural amino acid residue, andsalts/derivatives thereof in an acceptable suppository base. Thebiologically active cannabidiol analogs consist essentially ofbiologically active cannabidiol analogs disclosed hereinabove.

The suppository formulation of this invention can be suppositoryformulations in which the suppository base is a hydrophilic base or alipophilic base. The suppository formulation can advantageously comprisethe suppository formulation base which is a hydrophilic base such aspolyethylene glycol 1000.

The present invention also relates to a topical ophthalmic formulationbiologically active cannabidiol analogs for reducing the intraocularpressure and/or inflammation in the treatment of glaucoma or eyeinflammatory conditions, respectively. The formulation comprises atherapeutically effective amount of the present biologically activecannabidiol analogs and salts thereof in acceptable ophthalmic carrier.

A further embodiment of the invention relates to a Transmucosal DeliveryHot Melt Extrusion (HME) Patch formulation for the treatment of anydisease condition responsive to CBD. The formulation comprises atherapeutically effective amount of at least one compound of the presentbiologically active cannabidiol analog compositions.

Suppository bases can be classified per their physical characteristicsinto two main categories and a third miscellaneous group: (a) fatty oroleaginous bases, (b) water-soluble or water-miscible bases, and (c)miscellaneous bases, generally combinations of lipophilic andhydrophilic substances.

Among the fatty or oleaginous materials used in suppository bases arecocoa butter and many hydrogenated fatty acids of vegetable oils, suchas palm kernel oil and cottonseed oil. Also, fat-based compoundscontaining combinations of glycerin with the higher-molecular-weightfatty acids, such as palmitic and stearic acids, may be found in fattybases. Such compounds, such as glyceryl monostearate and glycerylmonopalmitate, are examples of this type of agent. The bases in manycommercial products employ varied combinations of these types ofmaterials to achieve the desired hardness under conditions of shipmentand storage and the desired quality of submitting to the temperature ofthe body to release their medicaments. Some bases are prepared with thefatty materials emulsified or with an emulsifying agent present toprompt emulsification when the suppository contacts the aqueous bodyfluids. These types of bases are arbitrarily placed in the third, ormiscellaneous, group of bases.

Cocoa Butter, NF, is defined as the fat obtained from the roasted seedof Theobroma cacao. At room temperature, it is a yellowish-white solidhaving a faint, agreeable chocolate-like odor. Chemically, it is atriglyceride (combination of glycerin and one or different fatty acids)primarily of oleopalmitostearin and oleodistearin.

Other bases in this category include commercial products such asFattibase (triglycerides from palm, palm kernel, and coconut oils withself-emulsifying glyceryl monostearate and polyoxyl stearate), theWecobee bases (triglycerides derived from coconut oil) and Witepsolbases (triglycerides of saturated fatty acids C12-C18 with variedportions of the corresponding partial glycerides).

The main members of water-soluble and water-miscible suppository basesare glycerinated gelatin and polyethylene glycols. Glycerinated gelatinsuppositories may be prepared by dissolving granular gelatin (20%) inglycerin (70%) and adding water or a solution or suspension of themedication (10%).

Polyethylene glycols are polymers of ethylene oxide and water preparedto various chain lengths, molecular weights, and physical states. Theyare available in several molecular weight ranges, the most commonly usedbeing polyethylene glycol 300, 400, 600, 1,000, 1,500, 1,540, 3,350,4,000, 6,000, and 8,000. The numeric designations refer to the averagemolecular weight of each of the polymers. Polyethylene glycols havingaverage molecular weights of 300, 400, and 600 are clear, colorlessliquids. Those having average molecular weights of greater than 1,000are wax like white solids whose hardness increases with an increase inthe molecular weight. Melting ranges for the polyethylene glycolsfollow:

300 −15° C.-18° C.  400 4° C.-8° C. 600 20° C.-25° C. 1000 37° C.-40° C.1450 43° C.-46° C. 3350 54° C.-58° C. 4600 57° C.-61° C. 6000 56° C.-63°C. 8000 60° C.-63° C.

Various combinations of these polyethylene glycols may be combined byfusion, using two or more of the various types to achieve a suppositorybase of the desired consistency and characteristics.

In the miscellaneous group of suppository bases are mixtures ofoleaginous and water-soluble or water-miscible materials. Thesematerials may be chemical or physical mixtures. Some are preformedemulsions, generally of the water-in-oil type, or they may be capable ofdispersing in aqueous fluids. One of these substances is polyoxyl 40stearate, a surface-active agent that is employed in several commercialsuppository bases. Polyoxyl 40 stearate is a mixture of the monostearateand distearate esters of mixed polyoxyethylene diols and the freeglycols, the average polymer length being equivalent to about 40oxyethylene units. The substance is a white to light tan waxy solid thatis water soluble. Its melting point is generally 39° C. to 45° C. (102°F. to 113° F.). Other surface-active agents useful in the preparation ofsuppository bases also fall into this broad grouping. Mixtures of manyfatty bases (including cocoa butter) with emulsifying agents capable offorming water-in-oil emulsions have been prepared. These bases holdwater or aqueous solutions and are said to be hydrophilic.

The preferred suppository bases in the present invention are watersoluble or water miscible bases.

The transmucosal device film or films (in the case of co-extrusion orlayering) generally comprises at least one water-soluble,water-swellable or water-insoluble thermoplastic polymer. Thethermoplastic polymer used to prepare the HME film may include, but isnot limited to polyethylene oxide (PolyOx®), polyvinylpyrrolidone(Kollidon®), hydroxypropyl cellulose (Klucel®), ethyl cellulose,methylcellulose, alkylcelluloses, veegums clays, alginates, PVP, alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose (e.g.,Avicel™), polacrillin potassium (e.g., Amberlite™), sodium alginate,corn starch, potato starch, pregelatinized starch, modified starch,cellulosic agents, montmorrilonite clays (e.g., bentonite), gums, agar,locust bean gum, gum karaya, pecitin, tragacanth, and other matrixformers known to those skilled in the art.

This matrix may optionally contain a bio adhesive (such as a Carbopol,polycarbophil, chitosan or others known to those skilled in the art—tofurther enhance the bio-adhesivity of the cannabinoid itself) or a bioadhesive layer may be laminated onto the matrix film or patch containingthe cannabinoid. In addition, an impermeable backing layer may beincorporated to insure unidirectional flow of the drug through thepatient's mucosa. In some cases, a rate controlling film or membrane mayalso be laminated or sprayed onto the cannabinoid-containing matrix tofurther control the rate of release of the actives.

The transmucosal preparation will preferably contain a ‘penetrationenhancer’ (which may also be referred to as an absorption enhancer orpermeability enhancer). These penetration enhancers may include bilesalts, such as sodium deoxycholate, sodium glycodeoxycholate, sodiumtaurocholate and sodium glycocholate, surfactants such as sodium laurylsulfate, Polysorbate 80, laureth-9, benzalkonium chloride,cetylpyridinium chloride and polyoxyethylene monoalkyl ethers such asthe BRIJ® and MYRJ® series. Additional penetration enhancers forinclusion in the embodiment include benzoic acids, such as sodiumsalicylate and methoxy salicylate, fatty acids, such as lauric acid,oleic acid, undecanoic acid and methyl oleate, fatty alcohols, such asoctanol and nonanol, laurocapram, the polyols, propylene glycol andglycerin, cyclodextrins, the sulfoxides, such as dimethyl sulfoxide anddodecyl methyl sulfoxide, the terpenes, such as menthol, thymol andlimonene, urea, chitosan and other natural and synthetic polymers.

The hot-melt extruded or hot-melt molded matrix may also comprise as bioadhesives such as water-soluble or water-swellable polymers derived fromacrylic acid or a pharmaceutically acceptable salt thereof, such as thepolyacrylic acid polymers, including carbomers, polycarbophils and/orwater-soluble salts of a co-polymer of methyl vinyl ether and maleicacid or anhydride (Gantrez MS-955).

The transmucosal preparation can also comprise one or more pH-adjustingagents to improve stability and solubility. Also, the pH modifyingagents can control cannabinoid release and enhance bio adhesion. ApH-adjusting agent can include, by way of example and withoutlimitation, an organic acid or base, an alpha-hydroxy acid, or abeta-hydroxy acid. Suitable agents include tartaric acid, citric acid,fumaric acid, succinic acid and others known to those of ordinary skillin the art.

The transmucosal preparation can also comprise one or more cross-linkingagents to reduce matrix erosion time, control release of the cannabinoidor enhance bio adhesion. A cross-linking agent can include, by way ofexample and without limitation, an organic acid, an alpha-hydroxy acid,or a beta-hemolytic-hydroxy acid. Suitable cross-linking agents includetartaric acid, citric acid, fumaric acid, succinic acid and others knownto those of ordinary skill in the art.

The transmucosal preparation may also contain other components thatmodify the extrusion, molding or casting characteristics or physicalproperties of the matrix. Such other components are well known to thoseof ordinary skill in the pharmaceutical sciences and include, forexample, polyethylene, xylitol, sucrose, surface-active agents, othersknown to those skilled in the art, and combinations thereof.

The transmucosal preparation of the present invention can also includesuper-disintegrants or absorbents. Examples of such are sodium starchglycolate (Explotab™, Primojel™) and croscarmellose sodium (Ac-Di-Sol®).Other suitable absorbents include cross-linked PVP (Polyplasdone™ XL10), clays, alginates, corn starch, potato starch, pregelatinizedstarch, modified starch, cellulosic agents, montmorrilonite clays(bentonite), gums, agar, locust bean gum, gum karaya, pectin,tragacanth, and other disintegrants known to those of ordinary skill inthe art.

The transmucosal preparation of the invention can include a chelatingagent. Suitable chelating agents include EDTA, polycarboxylic acids,polyamines, derivatives thereof, and others known to those of ordinaryskill in the art.

The transmucosal preparation of the invention can include a surfactant.Suitable surfactants include sucrose stearate, Vitamin E derivatives,sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and others knownto those of ordinary skill in the art.

The transmucosal preparation of the invention can include apreservative. Preservatives include compounds used to prevent the growthof microorganisms. Suitable preservatives include, by way of example andwithout limitation, benzalkonium chloride, propyl paraben, methylparaben, benzyl alcohol, cetylpridinium chloride, chlorobutanol, sorbicacid, phenol, phenylethyl alcohol, phenylmercuric nitrate and thimerosaland others known to those of ordinary skill in the art.

As used herein, the term “flavorant”, “flavor” or “fragrance” isintended to mean a compound used to impart a pleasant flavor and oftenodor to a pharmaceutical preparation, in addition to the naturalflavorants, many synthetic flavorants are also used. Such compoundsinclude, by way of example and without limitation, anise oil, cinnamonoil, cocoa, menthol, orange oil, peppermint oil and vanillin and othersknown to those of ordinary skill in the art. Flavors incorporated in thecomposition may be chosen from synthetic flavor oils and flavoringaromatics and/or natural oils, extract from plants, leaves, flowers,fruits and so forth and combinations thereof. These may include oil ofwintergreen, clove oil, bay oil, anise oil, eucalyptus, thyme oil, cedarleaf oil, oil of nutmeg, oil of sage, oil of bitter almonds and cassiaoil. Also, useful as flavors are vanilla, citrus oils, including lemon,orange, lime and grapefruit, and fruit essences, including grape, apple,pear, peach, strawberry, raspberry, cherry, plum, apricot, and so forth.Flavors that have been found to be particularly useful includecommercially available orange, grape, cherry, and bubble gum flavors andmixtures thereof. The amount of flavoring may depend on several factors,including the organoleptic effect desired.

As used herein, the term “colorant” is intended to mean a compound usedto impart color to solid pharmaceutical preparations. Such compoundsinclude, by way of example and without limitation, FD&C Red No. 3, FD&CRed No. 20, FD&C Yellow No. 6, FD&C Blue No. 2, D&C Green No. 5, D&COrange No. 5, D&C Red No. 8, caramel, and ferric oxide red. Othersuitable colorants include titanium dioxide and natural coloring agentssuch as grape extract, beet red powder, carmine, turmeric, paprika, andothers known to those of ordinary skill in the art.

The transmucosal preparation of the invention can include an antioxidantto prevent the deterioration of preparations by oxidation. Thesecompounds include, by way of example and without limitation, ascorbicacid, ascorbyl palmitate, butylated hydroxyanisole (BHA), butylatedhydroxytoluene (BHT), hypophophorous acid, monothioglycerol, sodiumascorbate, sodium formaldehyde sulfoxylate and sodium metabisulfate andothers known to those of ordinary skill in the art. Other suitableantioxidants include, for example, vitamin C, sodium bisulfite, vitaminE and its derivatives, propyl gallate, a sulfite derivative, and othersknown to those of ordinary skill in the art.

The transmucosal preparation of the invention may contain a release ratemodifier. Suitable release rate modifiers include hydroxypropylcellulose (HPC), poly (ethylene oxide) (PEO), hydroxypropylmethylcellulose (HPMC), ethyl cellulose, cellulosic polymers, acrylicpolymers, fat, waxes, lipid, or a combination thereof, hi someembodiments, the release rate modifier is polycarbophil, carbomer or apolysaccharide.

The ingredients and chemicals used to produce the transmucosalpreparation used in this invention are of acceptable quality, preferablypharmaceutically acceptable quality. The biologically active cannabidiolanalogs-containing transmucosal preparation is homogenous andpharmaceutically acceptable.

The transmucosal preparation of the invention can include stabilizers toprotect against hydrolysis. Such stabilizers may include cyclodextrins,chelating agents and surfactants.

The topical ophthalmic formulation can be solutions, emulsions, lipidnanoparticulate or matrix films. Other formulations known to one skilledin the art may also be used. The lipid nanoparticulate, emulsions andmatrix films are the most preferred formulations.

Solutions:

The solution formulations typically will require solubilizers in view ofthe low solubility of the cannabinoids. Examples of solubilizers thatcan be used in ophthalmic formulations include surfactants which formmicellar solutions (since the active ingredient is entrapped inmicelles) and complex forming agents or combinations thereof. Commonlyused surfactants in ophthalmic formulations include polyoxyethylenesorbates (e.g. Tween® 20 and Tween® 80), polyoxyl hydrogenated castoroils (e.g. Cremphor® EL and Cremophor® RH 40), Tyloxapol®,polyoxyethyelene ethers (Brij® series) and alkoxylated fatty acid esters(Myrj® series), sorbitan esters (Span® series) and others know to aperson skilled in the art. Cyclodextrins, such as hydroxypropylbetacyclodextrin and randomlymethylated beta cyclodextrins, are commonlyused to enhance solubility through inclusion complex formation. Thesolubilizers may be used alone or in combination.

Emulsions:

An emulsion is a system consisting of two immiscible liquid phases (oiland water), one of which is dispersed throughout the other as finedroplets, the system being stabilized by a third component, theemulsifying agent. Emulsions are inherently unstable, and emulsifiersare essential for both their initial formation and long-term stability.Emulsions may be oil in water (oil phase dispersed in the aqueous phase)or water in oil (water phase dispersed in the oil phase) emulsions. Avariety of other systems such as oil in water in oil emulsions and waterin oil in water emulsions are also known in the art. The oil phase mayconsist of oils such as soyabean oil, castor oil, sesame oil and oliveoil. Several emulsion stabilizers or emulsifying agents are known in theart and include surfactants and phospholipids. Examples of surfactantemulsifiers include polyoxyethylene sorbates (e.g. Tween® 20 and Tween®80), polyoxyl hydrogenated castor oils (e.g. Cremphor® EL and Cremophor®RH 40), Tyloxapol®, polyoxyethyelene ethers (Brij® series) andalkoxylated fatty acid esters (Myrj® series), sorbitan esters (Span®series) and others know to a person skilled in the art. Examples ofphospholipids that may be used as emulsion stabilizers includephospholipids (e.g. phosphatidylcholine, phosphatidylinositol,phosphatidylglycerol).

Lipid Nanoparticles:

Colloidal dispersions of solid lipid nanoparticles (SLNs) ornanostructured lipid carriers (NLCs) containing the therapeutic agentmay also be used. In these systems, the drug is loaded in the lipidphase, which is then dispersed in the aqueous phase. In the design ofSLNs, only lipids that are solid at room temperature are used whereaswith NLCs a combination of solid (e.g. Compritol®, Precirol®) and liquidlipids (e.g. Miglyol®) are used. Additionally, stabilizers such assurfactants and other components such as glycerine and propylene glycolmay also be used alone and in combination thereof.

Matrix Films:

Matrix films prepared using melt-extrusion or melt-cast technology canalso be used. The films comprise a thermoplastic polymer as the carrierof the active ingredient. The thermoplastic polymer used may include,but is not limited to polytheylene oxide (PolyOx®), polyvinylpyrrolidone(Kollidon®), hydroxypropyl cellulose (Klucel®), ethyl cellulose,methylcellulose, alkylcelluloses, veegums clays, alginates, PVP, alginicacid, carboxymethylcellulose calcium, microcrystalline cellulose (e.g.,Avicel™) polacrillin potassium (e.g., Amberlite™), sodium alginate, cornstarch, potato starch, pregelatinized starch, modified starch,cellulosic agents, montmorrilonite clays (e.g., bentonite), gums, agar,locust bean gum, gum karaya, pecitin, tragacanth, and other matrixformers known to those skilled in the art. The matrix film may alsocomprise of bioadhesives such as water-soluble or water-swellablepolymers derived from acrylic acid or a pharmaceutically acceptable saltthereof, such as the polyacrylic acid polymers, including carbomers,polycarbophils and/or water-soluble salts of a co-polymer of methylvinyl ether and maleic acid or anhydride (Gantrez MA-955).

The topical ophthalmic compositions may include additional oralternative polymeric ingredients and/or viscosity agents to increasestability and/or retention on the ocular surface. Examples includecarboxymethylcellulose, hydroxypropyl methyl cellulose, hydroxyethylcellulose, carboxyvinyl polymer, xanthan gum, hyaluronic acid, anycombinations thereof or the like.

The topical ophthalmic compositions may include a preservative.Potential preservatives include quaternary ammonium compounds such asbenzalkonium chloride, hydrogen peroxide and other ophthalmicpreservatives/preservative systems known in the art.

Other additives such as buffers and tonicity adjusting agents may alsobe included in the topical ophthalmic formulations. Examples ofbuffering agents include citrate, borate and acetate buffers. Tonicityadjusting agents may include for example sodium chloride and potassiumchloride. Additionally, stabilizers (e.g. antioxidants and chelatingagents) and penetration enhancers e.g. benzalkonium chloride, saponins,fatty acids, polyoxyethylene fatty ethers, alkyl esters of fatty acids,pyrrolidones, polyvinylpyrrolidone, pyruvic acids, pyroglutamic acidsand their mixtures, among others, may also be included.

The above description is only representative of illustrative embodimentsand examples. For the convenience of the reader, the above descriptionhas focused on a limited number of representative examples of allpossible embodiments, examples that teach the principles of theinvention. The description has not attempted to exhaustively enumerateall possible variations or even combinations of those variationsdescribed. That alternate embodiments may not have been presented for aspecific portion of the invention, or that further undescribed alternateembodiments may be available for a portion, is not to be considered adisclaimer of those alternate embodiments. One of ordinary skill willappreciate that many of those undescribed embodiments, involvedifferences in technology and materials rather than differences in theapplication of the principles of the invention. Accordingly, theinvention is not intended to be limited to less than the scope set forthin the following claims and equivalents.

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What we claim is:
 1. A pharmaceutical composition for pain managementcomprising a biologically active cannabidiol analog of the formula I

wherein one of R₁ or R₂ is H and the other is an amino acid ester amideor both R₁ and R₂ are an amino acid ester amide; or one of R₁ or R₂ isthe amino acid ester amide and the other R₁ or R₂ is the ester residueof a dicarboxylic acid or dicarboxylic acid-halide; wherein the aminoacid ester amide comprises an amino acid linked to one or both of thehydroxyl groups of cannabidiol through an ester linkage and adicarboxylic acid or dicarboxylic acid halide to the amino group of theamino acid in an amide linkage, wherein the amino acid is one ofAlanine, Arginine, Asparagine, Aspartic Acid, Cysteine, Glutamine,Glutamic Acid, Glycine, Histidine, Isoleucine, Leucine, Lysine,Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan,Tyrosine and Valine, and a pharmaceutically acceptable salt thereof. 2.The pharmaceutical composition for pain management according to claim 1,wherein the pain management is in an oncology setting.
 3. Thepharmaceutical composition of claim 1, wherein the dicarboxylic acid isan organic compound containing two carboxyl functional groups having theformula HO₂C—R—CO₂H, where R is a straight chain or branched aliphaticor aromatic lower alkyl.
 4. The pharmaceutical composition of claim 1,wherein the analog is CBD-Di-Alaninate-Di-Hemisuccinate,CBD-Divalinate-Di-Hemisuccinate, CBD-Mono-Valinate-Mono-Hemisuccinate,or CBD-monovalinate-dihemisuccinate.
 5. The pharmaceutical compositionof claim 1 wherein the analog is CBD-Divalinate-Di-Hemisuccinate, havingthe formula


6. The pharmaceutical composition of claim 1 wherein the analog isCBD-Monovalinate-Di-Hemisuccinate, having the formula


7. The pharmaceutical composition of claim 1 wherein the analog isCBD-Monovalinate-Mono-Hemisuccinate, having the formula


8. The pharmaceutical composition of claim 1 comprising the biologicallyactive cannabidiol analogs of claim 1 in a pharmaceutically acceptablecarrier.
 9. The pharmaceutical composition of claim 5 comprising thebiologically active cannabidiol analog of claim 5 in a pharmaceuticallyacceptable carrier.
 10. The pharmaceutical composition of claim 1,wherein the dicarboxylic acid is malonic acid, malic acid, glutaricacid, succinic acid, and phthalic acid.
 11. The pharmaceuticalcomposition of claim 7 comprising the biologically active cannabidiolanalog of claim 7 in a pharmaceutically acceptable carrier.